CN109608434B - Preparation method of lenalidomide - Google Patents
Preparation method of lenalidomide Download PDFInfo
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- CN109608434B CN109608434B CN201811609233.6A CN201811609233A CN109608434B CN 109608434 B CN109608434 B CN 109608434B CN 201811609233 A CN201811609233 A CN 201811609233A CN 109608434 B CN109608434 B CN 109608434B
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- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960004942 lenalidomide Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 9
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 132
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000003960 organic solvent Substances 0.000 claims description 33
- 238000001914 filtration Methods 0.000 claims description 28
- 238000005406 washing Methods 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 16
- 150000007530 organic bases Chemical class 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 11
- 239000008096 xylene Substances 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 10
- 239000012265 solid product Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical group CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 7
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 18
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 150000008064 anhydrides Chemical class 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- OGMCDJBYZAKJTP-UHFFFAOYSA-N methyl 2-(chloromethyl)-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1CCl OGMCDJBYZAKJTP-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 238000005984 hydrogenation reaction Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- QLGQENVLDXWTSX-UHFFFAOYSA-N 3-(4-nitrophenyl)-3H-2-benzofuran-1-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1C2=CC=CC=C2C(=O)O1 QLGQENVLDXWTSX-UHFFFAOYSA-N 0.000 description 9
- -1 4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl Chemical group 0.000 description 9
- DJMQLZPEBHSABD-UHFFFAOYSA-N 2-(methoxycarbonyl)-6-nitrobenzoic acid Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O DJMQLZPEBHSABD-UHFFFAOYSA-N 0.000 description 8
- BAJQRLZAPXASRD-UHFFFAOYSA-N 4-Nitrobiphenyl Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=CC=CC=C1 BAJQRLZAPXASRD-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 5
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical compound Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 description 4
- KFIRODWJCYBBHY-UHFFFAOYSA-N 3-nitrophthalic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O KFIRODWJCYBBHY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 208000015322 bone marrow disease Diseases 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- JKPJLYIGKKDZDT-UHFFFAOYSA-N 3-(7-nitro-3-oxo-1h-isoindol-2-yl)piperidine-2,6-dione Chemical compound C1C=2C([N+](=O)[O-])=CC=CC=2C(=O)N1C1CCC(=O)NC1=O JKPJLYIGKKDZDT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- JIMLDJNLXLMGLX-JTQLQIEISA-N (2s)-5-amino-5-oxo-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 JIMLDJNLXLMGLX-JTQLQIEISA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000008720 Bone Marrow Neoplasms Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000007698 birth defect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000004821 effect on bone Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical group C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- FCGIVHSBEKGQMZ-UHFFFAOYSA-N methyl 2-(bromomethyl)-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1CBr FCGIVHSBEKGQMZ-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing lenalidomide, which comprises the following steps: reacting the compound shown in the formula 1 with thionyl chloride and an alcohol solvent to obtain a compound shown in a formula 2; reacting the compound shown in the formula 2 with chloroformate to obtain anhydride, and then reducing to obtain a compound shown in a formula 3; reacting the compound shown in the formula 3 with a chlorination reagent to obtain a compound shown in a formula 4; carrying out condensation reaction on the compound shown in the formula 4 and the compound shown in the formula 5 to obtain a compound shown in a formula 6; the obtained compound shown in the formula 6 is reduced under the hydrogen condition to obtain lenalidomide shown in the formula 7. The method has the advantages of cheap and easily-obtained starting raw materials, short synthesis steps, simple operation, high yield, low production cost and easy industrial production.
Description
(I) technical field
The invention relates to the technical field of medicines. In particular, it relates to a process for the preparation of lenalidomide.
(II) technical background
Bone marrow disease is a hematological cancer, and any disease or condition that causes abnormal production of mature blood cells or progenitor cells of various lineages can cause bone marrow disease, with various abnormalities present. Although it is treatable, patients can suffer from severe mental injury after multiple chemotherapies, and the blood matching treatment is expensive, thus bringing huge burden to families of patients. Bone marrow diseases seriously threaten the life safety of people and become a strong enemy threatening the health of human beings.
Lenalidomide (lenalimide), which is sold under the trade name revlimide, has a chemical name of 3- (4-amino-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-dione, and has a structural formula shown in the specification. Lenalidomide is an immunomodulatory drug with multiple effects of anti-angiogenesis, immunomodulation and direct killing of tumor cells. It was developed by Celgene corporation, usa and received FDA approval in the united states at 12 months 2005 for the treatment of multiple myeloma and myelodysplastic syndrome. The composition is an enhanced version of thalidomide, has anticancer potential, has fewer adverse reactions compared with thalidomide, and is proved by research not to cause birth defects of infants.
Because of the curative effect on bone marrow tumor, the compound has wide market prospect, is a hot spot in the field of drug synthesis in recent years, attracts the attention of many chemists, and has been published in the synthesis. The three synthetic routes are divided according to different raw materials and intermediates, and a brief overview is carried out.
The document (Bioorganic & Medicinal Chemistry Letters,2011,21(3): 1019-. And NBS is adopted for bromination, polybromine substitutes can appear, and the reaction selectivity is poor.
Patent WO20060052609 takes N-carbobenzoxy-L-glutamine as a raw material, and generates an isoindoline ring by intermolecular condensation with 2-bromomethyl-3-nitrobenzoic acid methyl ester, then the condensation is carried out in a low-temperature molecule, and finally, nitro is reduced to obtain lenalidomide. The route has longer steps, fussy operation and higher cost, and is not beneficial to industrial production.
Patent CN101580501 uses 4-nitro-isoindole-1-ketone as raw material, through nitro reduction, condensation with a-dimethyl amyl bromide, ammonolysis and cyclization, lenalidomide is obtained. The method has the advantages of expensive raw materials, low yield, high cost and difficult industrial production.
Although a plurality of methods for preparing lenalidomide exist at present, the defects of complex preparation process, low synthesis efficiency, high production cost and the like exist. Thus, the current processes for preparing lenalidomide remain to be improved.
Disclosure of the invention
The invention aims to provide a novel method for synthesizing lenalidomide, which solves the problems of harsh reaction conditions, complex operation, serious pollution, low yield, unstable quality of finished products and difficult industrial production in the prior art.
In order to achieve the purpose, the invention adopts the following technical route:
a novel method for preparing lenalidomide shown as a formula 7, wherein the synthesis method comprises the following steps:
(a) reacting the compound shown in the formula 1 with thionyl chloride and an alcohol solvent to obtain a reaction solution A, and carrying out aftertreatment to obtain a compound shown in a formula 2;
(b) dissolving the compound shown in the formula 2 obtained in the step (a) in an organic solvent A, adding an organic base A and a chloroformate, reacting for 3-5 h at-15 ℃ (preferably-5 ℃), then slowly adding sodium borohydride, reacting for 1-5 h at-15-5 ℃ (preferably-5 ℃), adding methanol into the obtained product for quenching to obtain a reaction solution B, and carrying out post-treatment to obtain the compound shown in the formula 3; the mass ratio of the compound shown in the formula 2 to the organic base A and the chloroformic ether is 1: 1.0-5.0: 1.0 to 5.0 (preferably 1: 1.0 to 2.0);
(c) dissolving the compound shown in the formula 3 obtained in the step (B) in an organic solvent B, adjusting the temperature to 0 ℃, slowly dropwise adding thionyl chloride, stirring for 2 hours at 100-150 ℃ (preferably 120-135 ℃), distilling under reduced pressure, removing the organic solvent B and the thionyl chloride, cooling the obtained concentrated residue in a water bath, keeping the internal temperature at 60 ℃, dropwise adding methanol, stirring for 1 hour at 50 ℃, then cooling to 25 ℃, adding toluene, and obtaining a reaction solution C, and carrying out aftertreatment to obtain the compound shown in the formula 4; the mass ratio of the compound shown in the formula 3 to the substances of thionyl chloride and methanol is 1: 1-5: 1 to 10 (preferably 1: 1 to 2: 1 to 5);
(d) carrying out condensation reaction on the compound shown in the formula 4 obtained in the step (c) and the compound shown in the formula 5 to obtain a compound shown in a formula 6;
(e) and (d) reducing the compound shown in the formula 6 obtained in the step (d) under the hydrogen condition to obtain lenalidomide shown in the formula 7.
Further, specifically, the method in step (a) comprises: dissolving a compound shown as a formula 1 in an alcohol solvent, dropwise adding thionyl chloride in an ice bath, reacting for 4-8 hours at 30-100 ℃ (preferably 60-70 ℃) to obtain a reaction solution A, cooling to room temperature, adding water to remove the thionyl chloride, concentrating under reduced pressure, adding water to wash a concentrate, and performing suction filtration to obtain a compound shown as a formula 2; the mass ratio of the compound represented by the formula 1 to thionyl chloride is 1: 1 to 5 (preferably 1: 1 to 2); the alcohol solvent is methanol, ethanol, propanol and n-butanol, preferably methanol; the volume dosage of the alcohol solvent is 5-10 mL/g based on the mass of the compound shown in the formula 1.
Further, in the step (b), the organic solvent a is tetrahydrofuran, dichloromethane, chloroform, 2-methyltetrahydrofuran, toluene or ethyl acetate, preferably tetrahydrofuran; the volume dosage of the organic solvent A is 2-6 mL/g based on the mass of the compound shown in the formula 2.
Further, in the step (b), the organic base a is triethylamine, diethylamine, diisopropylethylamine or pyridine, preferably triethylamine.
Further, in step (b), the chloroformate is ethyl chloroformate, isobutyl chloroformate or tert-butyl chloroformate, preferably ethyl chloroformate.
Further, in the step (c), the organic solvent B is xylene, toluene, dichloromethane or tetrahydrofuran, preferably xylene; the volume dosage of the organic solvent B is 2-6 mL/g based on the mass of the compound shown in the formula 3.
Further, in the step (C), the post-treatment method of the reaction solution C comprises: the obtained reaction solution C was slowly dropped into a 3% by mass potassium carbonate aqueous solution, the toluene layer was separated and taken out, the obtained toluene layer was washed with saturated brine, and the mixture was concentrated under reduced pressure to obtain a compound represented by formula 4.
Further, the method in step (d) is: dissolving a compound shown as a formula 5 in an organic solvent C, adding an organic base B, stirring and mixing uniformly at room temperature to obtain a reaction mixture, adjusting the temperature to 80 ℃, dissolving the compound shown as a formula 4 obtained in the step (C) in the organic solvent C, slowly dripping the obtained mixture into the reaction mixture, preserving the temperature for 10 hours after dripping, cooling to room temperature, slowly adding water, stirring for 0.5 hour, filtering to obtain an off-white solid product, and drying to obtain a compound shown as a formula 6; the mass ratio of the compound shown in the formula 4 to the compound shown in the formula 5 and the organic base B is 1: 1.0-4: 1.0 to 5 (preferably 1: 1.2: 1.2); the organic base B is triethylamine, diethylamine, diisopropylethylamine or pyridine, preferably triethylamine.
Further, in the step (d), the organic solvent C is one or a mixture of any several of acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide or N, N-dimethylacetamide, preferably acetonitrile; the volume usage amount of the organic solvent C is 2-6 mL/g based on the mass of the compound shown in the formula 4.
Further, the method of step (e) is: dissolving the compound shown in the formula 6 obtained in the step (D) in an organic solvent D to obtain a mixed solution, adding a catalyst into the mixed solution, reacting for 5-8 hours at 10-50 ℃ (preferably 25 ℃) under the hydrogen pressure of 0.2-0.8 MPa to obtain a reaction solution E, and carrying out aftertreatment to obtain the compound shown in the formula 7; the catalyst is 5-10% Pd/C, 5-10% Pt/C or Raney nickel; the mass ratio of the compound shown in the formula 6 to the catalyst is 1: 0.01 to 0.2 (preferably 1: 0.05 to 0.1); the organic solvent D is methanol, ethanol, propanol or ethyl acetate, preferably methanol; the volume usage amount of the organic solvent D is 2-6 mL/g based on the mass of the compound shown in the formula 6.
In the present invention, the terms "reaction solution a", "reaction solution B", "reaction solution C", "reaction solution D", "reaction solution E", do not have a special meaning, and are labeled "a", "B", "C", "D", "E" only for distinguishing the reaction solutions mentioned in the different reaction steps; the terms "organic solvent a", "organic solvent B", "organic solvent C", "organic solvent D" have no special meaning, and are labeled "a", "B", "C", "D", "E" merely to distinguish the organic solvents mentioned in the different reaction steps; the terms "organic base a", "organic base B" have no special meaning and are labeled "a", "B" only to distinguish the organic bases mentioned in the different reaction steps.
Compared with the prior art, the invention has the beneficial effects that: the invention has the advantages of cheap and easily obtained starting material 3-nitrophthalic acid, short synthetic step, simple operation, high yield, low production cost and easy industrial production.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by the following examples, without restricting its scope.
Raney nickel of the present invention was purchased from CAS No.7440-02-0, Inc., of Raney Metal science and technology, Jiangsu.
Example 1: preparation of methyl 3-nitro-2-carboxybenzoate (Compound represented by formula 2)
Adding 250mL of methanol and 3-nitrophthalic acid (50g,236.8mmol) into a 500mL three-neck round-bottom flask, adjusting the temperature to-10 ℃, stirring to dissolve the mixture, slowly adding thionyl chloride (28g,236.8mmol), after the dropwise addition is finished, refluxing for 10 hours, wherein the solution is light yellow, detecting by TLC in the reaction process, stopping the reaction when the raw materials are completely reacted, cooling to room temperature, adding a small amount of water into the reaction solution, removing the thionyl chloride, concentrating under reduced pressure, washing the concentrate by adding large amount of water, and performing suction filtration to obtain 51.62g of a white solid product, wherein the yield is 96.7%. mp 162-;1H NMR(DMSO-d6):=14.10(1H,s),8.33(1H,d,J=8.17Hz),8.22(1H,d,J=7.72Hz)7.82(1H,dd,J=8.01,8.01Hz),3.33(3H,s)
example 2: preparation of methyl 3-nitro-2-carboxybenzoate (Compound represented by formula 2)
Adding 100mL of methanol and 3-nitrophthalic acid (20g,94.3mmol) into a 250mL three-neck round-bottom flask, adjusting the temperature to-10 ℃, stirring to dissolve the mixture, slowly adding thionyl chloride (16.8g,141.5mmol), after the dropwise addition is finished, refluxing for 10 hours, wherein the solution is light yellow, detecting by TLC in the reaction process, stopping the reaction when the raw materials are completely reacted, cooling to room temperature, adding a small amount of water into the reaction solution, removing thionyl chloride, concentrating under reduced pressure, adding a large amount of water to wash the concentrate, and performing suction filtration to obtain 21g of a white solid product, wherein the yield is 98.4%. mp 162-;
example 3: preparation of methyl 3-nitro-2-carboxybenzoate (Compound represented by formula 2)
Adding 150mL of methanol and 3-nitrophthalic acid (30g,142.2mmol) into a 250mL three-neck round-bottom flask, adjusting the temperature to-10 ℃, stirring to dissolve the mixture, slowly adding thionyl chloride (33.8g,284.4mmol), after the dropwise addition is finished, refluxing for 10 hours, wherein the solution is light yellow, detecting by TLC in the reaction process, stopping the reaction when the raw materials are completely reacted, cooling to room temperature, adding a small amount of water into the reaction solution, removing thionyl chloride, concentrating under reduced pressure, adding a large amount of water to wash the concentrate, and performing suction filtration to obtain 31g of a white solid product, wherein the yield is 96.9%. mp 162-164 ℃ (mp 160-162 ℃);
example 4: preparation of 4-nitrophenylphthalide (compound represented by formula 3)
Adding 20mL of tetrahydrofuran, 3-nitro-2-carboxybenzoic acid methyl ester (1g,4.5mmol) into a 50mL three-neck round-bottom flask, stirring to dissolve the mixture clearly, adjusting the temperature to-10 ℃, slowly adding triethylamine (0.448g,4.5mmol), dripping for 10min, under the protection of nitrogen, slowly adding ethyl chloroformate (0.6g, 4.4mmol), after adding for 5min, reacting the solution in a milky suspension at room temperature, detecting TCL (PE: EA is 4: 1), completely reacting the raw materials, performing suction filtration, removing triethylamine hydrochloride, adding the filtrate into a 50mL three-neck round-bottom flask, adjusting the temperature to-10 ℃, slowly adding sodium borohydride (0.168g, 4.5mol), dripping 2mL of methanol, and detecting TCL (PE: EA is 4: 1) until the raw materials completely react. Quenched with 2mL of saturated ammonium chloride, concentrated under reduced pressure, washed with saturated brine, extracted with dichloromethane, and the organic phases combined. 0.6g of crude product was obtained in 75.4% yield. mp 151-154 ℃,1HNMR(400MHz,CDCl3):=8.55(d,J=8.0Hz,1H),8.29(d,J=7.6Hz,1H),7.83(t,J=8.0Hz,1H),5.78(s,2H).
example 5: preparation of 4-nitrophenylphthalide (compound represented by formula 3)
Adding 20mL of tetrahydrofuran, 3-nitro-2-carboxybenzoic acid methyl ester (1g,4.5mmol) into a 50mL three-neck round-bottom flask, stirring to dissolve the mixture clearly, adjusting the temperature to-10 ℃, slowly adding triethylamine (0.448g,4.5mmol), dripping for 10min, under the protection of nitrogen, slowly adding ethyl chloroformate (0.729g, 6.75mmol), after finishing the addition for 5min, reacting the solution in a milky suspension at room temperature, detecting TCL (PE: EA is 4: 1), completely reacting the raw materials, performing suction filtration, removing triethylamine hydrochloride, adding the filtrate into a 50mL three-neck round-bottom flask, under the protection of nitrogen, adjusting the temperature to-10 ℃, slowly adding sodium borohydride (0.168g, 4.5mol), dripping methanol 2mL, and detecting TCL (PE: EA is 4: 1) until the raw materials completely react. Quenched with 2mL of saturated ammonium chloride, concentrated under reduced pressure, washed with saturated brine, extracted with dichloromethane, and the organic phases combined. 0.65g of crude product was obtained with a yield of 81.7%. mp 151-.
Example 6: preparation of 4-nitrophenylphthalide (compound represented by formula 3)
Adding 20mL of tetrahydrofuran, 3-nitro-2-carboxybenzoic acid methyl ester (1g,4.5mmol) into a 50mL three-neck round-bottom flask, stirring to dissolve the mixture clearly, adjusting the temperature to-10 ℃, slowly adding triethylamine (0.448g,4.5mmol), dripping for 10min, under the protection of nitrogen, slowly adding ethyl chloroformate (0.972g, 9mmol), after 5min, adding the solution to a milky suspension, reacting at room temperature, detecting TCL (PE: EA ═ 4: 1), completely reacting the raw materials, performing suction filtration, removing triethylamine hydrochloride, adding the filtrate into a 50mL three-neck round-bottom flask, adjusting the temperature to-10 ℃, slowly adding sodium borohydride (0.168g, 4.5mol), dripping 2mL of methanol, and detecting the TCL (PE: EA ═ 4: 1) until the raw materials completely react. Quenching by adding 2mL of saturated ammonium chloride, concentrating under reduced pressure, washing with saturated brine, extracting with dichloromethane, combining organic phases, and concentrating under reduced pressure to obtain 0.66g of crude product with the yield of 82.9%. mp 151-154 ℃.
Example 7: preparation of 4-nitrophenylphthalide (compound represented by formula 3)
Adding 20mL of tetrahydrofuran, 3-nitro-2-carboxybenzoic acid methyl ester (1g,4.5mmol) into a 50mL three-neck round-bottom flask, stirring to dissolve the mixture clearly, adjusting the temperature to-10 ℃, slowly adding triethylamine (0.448g,4.5mmol), dripping for 10min, under the protection of nitrogen, slowly adding ethyl chloroformate (0.729g, 6.75mmol), after finishing the addition for 5min, reacting the solution in a milky suspension at room temperature, detecting TCL (PE: EA is 4: 1), completely reacting the raw materials, performing suction filtration, removing triethylamine hydrochloride, adding the filtrate into a 50mL three-neck round-bottom flask, under the protection of nitrogen, adjusting the temperature to-10 ℃, slowly adding sodium borohydride (0.262g, 6.75mmol), dripping methanol 2mL, and detecting TCL (PE: EA is 4: 1) until the raw materials completely react. Quenching by adding 2mL of saturated ammonium chloride, concentrating under reduced pressure, washing with saturated brine, extracting with dichloromethane, combining organic phases, and concentrating under reduced pressure to obtain 0.68g of crude product with the yield of 85.47%. mp 151-.
Example 8: preparation of 4-nitrophenylphthalide (compound represented by formula 3)
Adding 20mL of tetrahydrofuran, 3-nitro-2-carboxybenzoic acid methyl ester (1g,4.5mmol) into a 50mL three-neck round-bottom flask, stirring to dissolve the mixture clearly, adjusting the temperature to-10 ℃, slowly adding triethylamine (0.448g,4.5mmol), dripping for 10min, under the protection of nitrogen, slowly adding ethyl chloroformate (0.729g, 6.75mmol), after finishing the addition for 5min, reacting the solution in a milky suspension at room temperature, detecting TCL (PE: EA is 4: 1), completely reacting the raw materials, performing suction filtration, removing triethylamine hydrochloride, adding the filtrate into a 50mL three-neck round-bottom flask, under the protection of nitrogen, adjusting the temperature to-10 ℃, slowly adding sodium borohydride (0.34g, 9mmol), dripping 2mL of methanol, and detecting the TCL (PE: EA is 4: 1) until the raw materials completely react. Quenching by adding 2mL of saturated ammonium chloride, concentrating under reduced pressure, washing with saturated brine, extracting with dichloromethane, combining organic phases, and concentrating under reduced pressure to obtain 0.65g of crude product with the yield of 87.9%. mp 151-154 ℃.
Example 9: preparation of methyl 2-chloromethyl-3-nitrobenzoate (compound represented by formula 4)
100mL of xylene and 4-nitrophenylphthalide (17.9g, 0.1mol) were added to a 250mL three-necked flask, the temperature was adjusted to 0 ℃, thionyl chloride (14.28g, 0.12mol) was slowly added dropwise, and the mixture was stirred at 125-132 ℃ for 2 hours. The xylene and excess thionyl chloride were removed by distillation under reduced pressure, and the resulting concentrated residue was cooled with a water bath while maintaining the internal temperature at 60 ℃, methanol (8.01g, 0.25mol) was added dropwise, further stirred at 50 ℃ for 1 hour, then cooled to 25 ℃, and 300mL of toluene was added. Then, the reaction solution was slowly dropped into 300mL of a 3% by mass aqueous solution of potassium carbonate. Separating toluene layer, and collectingThe toluene layer was washed with saturated brine, and concentrated under reduced pressure to give 15g of methyl 2-chloromethyl-3-nitrobenzoate in a yield of 65.5%.1HNMR(500MHz,CDCl3):=8.09(dd,J=7.5,2.0Hz,1H),8.04(dd,J=7.5,2.0Hz,1H),7.51(t,J=7.5Hz,1H),4.64(s,2H),3.94(s,3H).
Example 10: preparation of methyl 2-chloromethyl-3-nitrobenzoate (compound represented by formula 4)
100mL of xylene and 4-nitrophenylphthalide (17.9g, 0.1mol) were added to a 250mL three-necked flask, the temperature was adjusted to 0 ℃, thionyl chloride (11.9g, 0.1mol) was slowly added dropwise, and the mixture was stirred at 125-132 ℃ for 2 hours. The xylene and excess thionyl chloride were removed by distillation under reduced pressure, and the resulting concentrated residue was cooled with a water bath while maintaining the internal temperature at 60 ℃, methanol (8.01g, 0.25mol) was added dropwise, further stirred at 50 ℃ for 1 hour, then cooled to 25 ℃, and 300mL of toluene was added. Then, the reaction solution was slowly dropped into 300mL of a 3% by mass aqueous solution of potassium carbonate. The toluene layer was separated and taken out, and the obtained toluene layer was washed with saturated brine and concentrated under reduced pressure to obtain 13g of methyl 2-chloromethyl-3-nitrobenzoate with a yield of 56.7%.
Example 11: preparation of methyl 2-chloromethyl-3-nitrobenzoate (compound represented by formula 4)
100mL of xylene and 4-nitrophenylphthalide (17.9g, 0.1mol) were added to a 250mL three-necked flask, the temperature was adjusted to 0 ℃, thionyl chloride (23.8g, 0.2mol) was slowly added dropwise, and the mixture was stirred at 125-132 ℃ for 2 hours. The xylene and excess thionyl chloride were removed by distillation under reduced pressure, and the resulting concentrated residue was cooled with a water bath while maintaining the internal temperature at 60 ℃, methanol (8.01g, 0.25mol) was added dropwise, further stirred at 50 ℃ for 1 hour, then cooled to 25 ℃, and 300mL of toluene was added. Then, the reaction solution was slowly dropped into 300mL of a 3% by mass aqueous solution of potassium carbonate. The toluene layer was separated and taken out, and the obtained toluene layer was washed with saturated brine and concentrated under reduced pressure to obtain 15.6g of methyl 2-chloromethyl-3-nitrobenzoate in 68% yield.
Example 12: preparation of methyl 2-chloromethyl-3-nitrobenzoate (compound represented by formula 4)
100mL of toluene and 4-nitrophenylphthalide (17.9g, 0.1mol) were added to a 250mL three-necked flask, the temperature was adjusted to 0 ℃, thionyl chloride (14.28g, 0.12mol) was slowly added dropwise, and the mixture was stirred at 125-132 ℃ for 2 hours. The residue was cooled in a water bath while maintaining the internal temperature at 60 ℃ and methanol (8.01g, 0.25mol) was added dropwise, followed by stirring at 50 ℃ for 1 hour, cooling to 25 ℃ and addition of 300mL of toluene. Then, the reaction solution was slowly dropped into 300mL of a 3% by mass aqueous solution of potassium carbonate. The toluene layer was separated and taken out, and the obtained toluene layer was washed with saturated brine and concentrated under reduced pressure to obtain 14g of methyl 2-chloromethyl-3-nitrobenzoate in a yield of 61%.
Example 13: preparation of 3- (4-nitro-1, 3-dihydro-1-oxo-2-hydro-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 6)
Adding 3-amino-2, 6-piperidinedione hydrochloride (1.7g, 0.0115mol), triethylamine (4.48g,0.045mol) and 10mL of acetonitrile into a three-necked bottle, stirring and mixing uniformly at room temperature, adjusting the temperature to 80 ℃, dissolving 2-chloromethyl-3-nitrobenzoic acid methyl ester (2.2g, 0.0096mol) into 20mL of acetonitrile, slowly dropwise adding into the reaction solution, preserving the temperature for 10h after dropwise adding, cooling to room temperature, slowly adding 50mL of water, stirring for 0.5h, filtering to obtain an off-white solid product, and drying to obtain 2g of 3- (4-nitro-1, 3-dihydro-1-oxo-2 hydrogen-isoindol-2-yl) piperidine-2, 6-dione with the yield of 93.2%.1H NMR(DMSO-d6):=11.03(s,1H),8.45(d,J=7.8H z,1H),8.17(d,J=7.2Hz,1H),7.83(t,1H),5.16(d,J=12.9Hz,4.5Hz,1H),4.88(dd,J=36.9Hz,J=18.8Hz,2H),2.84~2.96(m,1H),2.55~2.61(m,1H),2.45~2.51(m,1H),1.98~2.02(m,1H).
Example 14: preparation of 3- (4-nitro-1, 3-dihydro-1-oxo-2-hydro-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 6)
Adding 3-amino-2, 6-piperidinedione hydrochloride (1.7g, 0.0115mol), triethylamine (2g,0.020mol) and 10mL of acetonitrile into a three-necked bottle, stirring and mixing uniformly at room temperature, adjusting the temperature to 80 ℃, dissolving 2-chloromethyl-3-nitrobenzoic acid methyl ester (2.2g, 0.0096mol) into 20mL of acetonitrile, slowly dropwise adding the mixture into the reaction solution, preserving the temperature for 10 hours after dropwise adding, cooling to room temperature, slowly adding 50mL of water, stirring for 0.5 hour, filtering to obtain an off-white solid product, and drying to obtain 1.9g of 3- (4-nitro-1, 3-dihydro-1-oxo-2 hydro-isoindol-2-yl) piperidine-2, 6-dione with the yield of 88.5%.
Example 15: preparation of 3- (4-nitro-1, 3-dihydro-1-oxo-2-hydro-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 6)
Adding 3-amino-2, 6-piperidinedione hydrochloride (1.7g, 0.0115mol), triethylamine (1g,0.010mol) and 10mL of acetonitrile into a three-necked bottle, stirring and mixing uniformly at room temperature, adjusting the temperature to 80 ℃, dissolving 2-chloromethyl-3-nitrobenzoic acid methyl ester (2.2g, 0.0096mol) into 20mL of acetonitrile, slowly dropwise adding the mixture into the reaction solution, preserving the temperature for 10 hours after dropwise adding, cooling to room temperature, slowly adding 50mL of water, stirring for 0.5 hour, filtering to obtain an off-white solid product, and drying to obtain 1.5g of 3- (4-nitro-1, 3-dihydro-1-oxo-2 hydro-isoindol-2-yl) piperidine-2, 6-dione with the yield of 70%.
Example 16: preparation of 3- (4-nitro-1, 3-dihydro-1-oxo-2-hydro-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 6)
Adding 3-amino-2, 6-piperidinedione hydrochloride (1.57g, 0.0096mol), triethylamine (2g,0.020mol) and 10mL of acetonitrile into a three-necked bottle, stirring and mixing uniformly at room temperature, adjusting the temperature to 80 ℃, dissolving 2-chloromethyl-3-nitrobenzoic acid methyl ester (2.2g, 0.0096mol) into 20mL of acetonitrile, slowly dropwise adding the mixture into the reaction solution, preserving the temperature for 10 hours after dropwise adding, cooling to room temperature, slowly adding 50mL of water, stirring for 0.5 hour, filtering to obtain an off-white solid product, and drying to obtain 1.46g of 3- (4-nitro-1, 3-dihydro-1-oxo-2 hydro-isoindol-2-yl) piperidine-2, 6-dione with the yield of 68%.
Example 17: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.5g 10% Pd/C, 200mL methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, drying the filter cake to obtain 1.5g of light yellow solid, wherein the yield is 83.6%. m.p. 246-248 deg.CThe document is as follows: 235.5 to 239.0 ℃).1H NMR(DMSO-d6):=2.00~2.08(m,1H),2.25~2.3 6(m,1H),2.60~2.64(m,1H),2.88~2.97(m,1H),4.16(dd,2H,J=40.0Hz,J=17.2Hz),5.11(dd,1H,J=13.2Hz,J=5.2Hz),5.41(s,2H),6.80(d,1H,J=7.6Hz),6.92(d,1H,J=7.6Hz),7.19(t,1H,J=7.6Hz),10.99(s,1H)。EI-MS(m/z):259(M+),214,147,104。
Example 18: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.28g 10% Pd/C, 200mL methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, drying the filter cake to obtain 1.3g of light yellow solid, wherein the yield is 72.5%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 19: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.3g 10% Pd/C, 200mL ethanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL ethanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, drying the filter cake to obtain 1.4g of light yellow solid, wherein the yield is 78.1%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 20: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.3g 10% Pd/C, 200mL methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.5g of light yellow solid with the yield of 83.68%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 21: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.2g of 10% Pt/C, 200mL of methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL of methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL of hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.2g of light yellow solid with the yield of 66.94%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 22: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.3g of 10% Pt/C, 200mL of methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL of methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL of hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.33g of light yellow solid with the yield of 74.2%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 23: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.25g of 10% Pt/C, 200mL of methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL of methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL of hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.23g of light yellow solid with the yield of 68.62%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 24: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-dione (2g,0.007mol), 0.5g raney nickel, 200mL methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.6g of light yellow solid with the yield of 89.26%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 25: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.4g raney nickel, 200mL methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.5g of light yellow solid with the yield of 83.68%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 26: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-diketone (2g,0.007mol), 0.3g raney nickel, 200mL methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.48g of light yellow solid with the yield of 82.57%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Example 27: preparation of 3- (4-amino-1, 3-dihydro-1-oxo-2 h-isoindol-2-yl) piperidine-2, 6-dione (compound represented by formula 7)
Adding 3- (4-nitro-1, 3-dihydro-1-oxo-2H-isoindol-2-yl) piperidine-2, 6-dione (2g,0.007mol), 0.2g raney nickel, 200mL methanol and 1.2MP hydrogen pressure into a 500mL hydrogenation reaction kettle, reacting at 25 ℃ for 10h, filtering, washing filter residues with 20mL methanol, concentrating the filtrate under reduced pressure to dryness, washing with 50mL hot ethyl acetate for 30min, filtering, and drying the filter cake to obtain 1.32g of light yellow solid with the yield of 82.57%. m.p. 246 to 248 deg.C (document: 235.5 to 239.0 deg.C).
Claims (10)
1. A process for preparing lenalidomide of formula 7, comprising: the method comprises the following steps:
(a) reacting a compound shown in a formula 1 with thionyl chloride and an alcohol solvent to obtain a reaction solution A, and performing aftertreatment to obtain a compound shown in a formula 2, wherein the mass ratio of the compound shown in the formula 1 to the thionyl chloride is 1: 1-5;
(b) dissolving the compound shown in the formula 2 obtained in the step (a) in an organic solvent A, adding an organic base A and chloroformate, reacting at-15 ℃ for 3-5 h, then slowly adding sodium borohydride, reacting at-15-5 ℃ for 1-5 h, adding methanol into the obtained product, quenching to obtain a reaction solution B, and carrying out aftertreatment to obtain the compound shown in the formula 3; the mass ratio of the compound shown in the formula 2 to the organic base A and the chloroformic ether is 1: 1.0-5.0: 1.0 to 5.0;
(c) dissolving the compound shown in the formula 3 obtained in the step (B) in an organic solvent B, adjusting the temperature to 0 ℃, slowly dropwise adding thionyl chloride, stirring for 2 hours at the temperature of 100-150 ℃, distilling under reduced pressure, removing the organic solvent B and the thionyl chloride, cooling the obtained concentrated residue by using a water bath, keeping the internal temperature at 60 ℃, dropwise adding methanol, stirring for 1 hour at 50 ℃, then cooling to 25 ℃, adding toluene, and obtaining a reaction solution C, and carrying out aftertreatment to obtain the compound shown in the formula 4; the mass ratio of the compound shown in the formula 3 to the substances of thionyl chloride and methanol is 1: 1-5: 1-10;
(d) carrying out condensation reaction on the compound shown in the formula 4 obtained in the step (c) and the compound shown in the formula 5 to obtain a compound shown in a formula 6;
(e) reducing the compound shown in the formula 6 obtained in the step (d) under the hydrogen condition to obtain lenalidomide shown in a formula 7;
the alcohol solvent is methanol, and R1 is methyl.
2. The method of claim 1, wherein: the method in the step (a) comprises the following steps: dissolving a compound shown as a formula 1 in an alcohol solvent, dropwise adding thionyl chloride in an ice bath, reacting at 30-100 ℃ for 4-8 hours to obtain a reaction solution A, cooling to room temperature, adding water to remove the thionyl chloride, concentrating under reduced pressure, washing a concentrate with increased amount of water, and performing suction filtration to obtain a compound shown as a formula 2; the volume dosage of the alcohol solvent is 5-10 mL/g based on the mass of the compound shown in the formula 1.
3. The method of claim 1, wherein: in the step (b), the organic solvent A is tetrahydrofuran, dichloromethane, trichloromethane, 2-methyltetrahydrofuran, toluene or ethyl acetate; the volume dosage of the organic solvent A is 2-6 mL/g based on the mass of the compound shown in the formula 2.
4. The method of claim 1, wherein: in the step (b), the organic base A is triethylamine, diethylamine, diisopropylethylamine or pyridine.
5. The method of claim 1, wherein: in the step (b), the chloroformate is ethyl chloroformate, isobutyl chloroformate or tert-butyl chloroformate.
6. The method of claim 1, wherein: in the step (c), the organic solvent B is xylene, toluene, dichloromethane or tetrahydrofuran; the volume dosage of the organic solvent B is 2-6 mL/g based on the mass of the compound shown in the formula 3.
7. The method of claim 1, wherein: in the step (C), the post-treatment method of the reaction solution C comprises the following steps: the obtained reaction solution C was slowly dropped into a 3% by mass potassium carbonate aqueous solution, the toluene layer was separated and taken out, the obtained toluene layer was washed with saturated brine, and the mixture was concentrated under reduced pressure to obtain a compound represented by formula 4.
8. The method of claim 1, wherein: the method in the step (d) comprises the following steps: dissolving a compound shown as a formula 5 in an organic solvent C, adding an organic base B, stirring and mixing uniformly at room temperature to obtain a reaction mixture, adjusting the temperature to 80 ℃, dissolving the compound shown as a formula 4 obtained in the step (C) in the organic solvent C, slowly dripping the obtained mixture into the reaction mixture, preserving the temperature for 10 hours after dripping, cooling to room temperature, slowly adding water, stirring for 0.5 hour, filtering to obtain an off-white solid product, and drying to obtain a compound shown as a formula 6; the mass ratio of the compound shown in the formula 4 to the compound shown in the formula 5 and the organic base B is 1: 1.0-4: 1.0 to 5; the organic base B is triethylamine, diethylamine, diisopropylethylamine or pyridine.
9. The method of claim 8, wherein: in the step (d), the organic solvent C is one or a mixture of any more of acetonitrile, dichloromethane, trichloromethane, 1, 2-dichloroethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide or N, N-dimethylacetamide; the volume usage amount of the organic solvent C is 2-6 mL/g based on the mass of the compound shown in the formula 4.
10. The method of claim 1, wherein: the method of the step (e) comprises the following steps: dissolving the compound shown in the formula 6 obtained in the step (D) in an organic solvent D to obtain a mixed solution, adding a catalyst into the mixed solution, reacting at 10-50 ℃ for 5-8 hours under the hydrogen pressure of 0.2-0.8 MPa to obtain a reaction solution E, and carrying out aftertreatment to obtain a compound shown in a formula 7; the catalyst is 5-10% Pd/C, 5-10% Pt/C or Raney nickel; the mass ratio of the compound shown in the formula 6 to the catalyst is 1: 0.01 to 0.2; the organic solvent D is methanol, ethanol, propanol or ethyl acetate; the volume usage amount of the organic solvent D is 2-6 mL/g based on the mass of the compound shown in the formula 6.
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